1. Field of the Invention
The present invention relates to a device and a method of inducing and maintaining vascularization near an implant for the purpose of facilitating the formation of ultrafiltrate as well as facilitating the transport of oxygen, nutrients and metabolites to/from cells in the implant. More specifically, this invention relates to a device and a method of maintaining vascularization near a bioartificial hemofilter.
2. Discussion of the Background
One traditional approach to development of a bioartificial filtration device is to promote site-directed neovascularization in vivo near a mechanism for removing filtrate (see, for example, J. A. Thompson et al., Science 241, p. 1349-1352, 1988, the contents of which are incorporated herein by reference). In this approach, angiogenic factors (J. Folkman, and Y. Shing, J Biol. Chem. 267(16), p. 10931-10934, 1992 the contents of which are incorporated herein by reference) are delivered via exogenous and endogenous routes in order to induce targeted angiogenesis around and among implanted biocompatible hollow fibers. These hollow fibers are envisioned to act as collecting (drainage) conduits of ultrafiltrate produced by the newly-formed capillary network induced by the angiogenic factors. This formulation relies upon the intrinsic properties inherent to all capillary beds that allow them to produce ultrafiltrate when a pressure differential is applied across the capillary bed. This filtrate, or transudate, will collect in the hollow fiber network rather than the usual physiologic sites consisting of the interstitial space and lymphatics. In other words, the vectorial filtrate flow will be from capillary through interstitium into hollow fiber, since the hydraulic pressure difference from capillary lumen to hollow fiber can be greater than 20 mm Hg when the hollow fiber system is connected to an drainage and collection system. Once the filtrate is collected in the hollow fiber network, it can be drawn from the body, thereby mimicking some of the filtration properties of, for example, the kidney.
The inventor has realized that once the administration of angiogenic factors (compounds that spur neovascularization) to such systems is discontinued, the newly formed capillary beds regress from the hollow fibers that collect the ultrafiltrate. Regression decreases blood flow to the hollow fiber network and increases the effective resistance to flow along the path from capillary lumen to hollow fiber. The net result is a decrease in the flow rate of filtrate along this path and a decrease in the clearance of various compounds from the body.
Inducing vascularization in the surroundings is also important in other types of implants. For example, encapsulated cell implants often suffer from a poor supply of nutrients and/or removal of metabolites from the implants themselves. This commonly leads to encapsulated cell necrosis and reduced production of cellular products. The major reason underlying the poor transport characteristics of implants is that, in contrast to normal tissues, typical tissue-engineered implants are characterized primarily by diffussive rather than convective mass transport processes. Even when designers incorporate convective transport (see for example Pillarella and Zydney, J Biomech Eng 112(2):220-8, 1990, incorporated herein by reference) by grafting the implant to the vasculature, transport rates are still trailing those of native tissues because the latter possess an extensive microvasular network. By spurring vascularization in and around such implants, however, more facile transport of metabolites and/or nutrients to and from the implants can be achieved.
Furthermore, the inventor has realized that ultrafiltrate formed in a hemofilter such as the vascularized implant described in this invention, may provide a supply of nutrients and oxygen via convective transport to cell implants, while denying access of immunoglobulins, immune cells, and complement proteins to the implanted cells, thereby avoiding the immunologic consequences of blood contact with implanted cells.